Although treatments in animal models for HD have proven successful, and several clinical trials are underway in persons with manifest HD, there currently exists no methodology in which to test experimental therapeutics prior to diagnosis of manifest motor disease. The Predict-HD study is designed to provide essential methodology for the initiation of preventive clinical trials in Huntington's disease (HD). Early identification of neurological disease is imperative so that intervention using protective, gene therapy, and regenerative strategies can be initiated at high levels of life quality and prior to the occurence of irreversible cellular injury. The Predict-HD study has successfully recruited nearly 500 healthy participants who had previously undergone genetic testing for the HD expansion. Annual measures of brain imaging and cognitive performance are obtained in concert with other demographic, clinical and genetic information. Findings already suggest a remarkable convergence of the first detectable decline in brain morphology, motor skill, and cognitive ability at about 15 years prior to traditional motor diagnosis. This is notably earlier than had generally suspected and represents a major advance in our understanding of HD. With completion of the requested 3-year continuation of the Predict-HD study we will have longitudinal observations that allow us to: 1) Test and refine the model of early HD changes suggested by our baseline data; 2) Determine which measures of functional decline are concurrent with measureable brain morphology changes; and 3) Better understanding of the relationships among striatal and cortical changes, DNA repeat length, and clinical phenotype in HD. Completion of Predict-HD will result in a methodology and a cohort that can be readily applied to presymptomatic treatments as they become available. In addition to the contribution this will make towards early intervention in HD, our findings are likely to improve our understanding of the functional pathophysiology of other neurodegenerative and genetic illnesses.